title: Androgen and PARP-1 regulation of TRPM2 channels after ischemic injury.
abstract: The calcium-permeable transient receptor potential M2 (TRPM2) ion channel was recently demonstrated to have a sexually dimorphic contribution to ischemic brain injury, with inhibition or knockdown of the channel protecting male brain preferentially. We tested the hypothesis that androgen signaling is required for this male-specific cell-death pathway. Additionally, we tested the hypothesis that differential activation of the enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is responsible for male-specific TRPM2 channel activation and neuronal injury. We observed that administration of the TRPM2 inhibitor clotrimazole (CTZ) 2 hours after onset of ischemia reduced infarct volume in male mice and that protection from ischemic damage by CTZ was abolished by removal of testicular androgens (castration; CAST) and rescued by androgen replacement. Male PARP-1 knockout mice had reduced ischemic damage compared with WT mice and inhibition of TRPM2 with CTZ failed to reduce infarct size. Lastly, we observed that ischemia increased PARP activity in the peri-infarct region of male mice to a greater extent than female mice and the difference was abolished in CAST male mice. Data presented in the current study indicate that TRPM2-mediated neuronal death in the male brain requires intact androgen signaling and PARP-1 activity.
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Takeru
authors.initials: T
authors.lastname: Shimizu
authors.forename: Tara A
authors.initials: TA
authors.lastname: Macey
authors.forename: Nidia
authors.initials: N
authors.lastname: Quillinan
authors.forename: Jelena
authors.initials: J
authors.lastname: Klawitter
authors.forename: Anne-Laure L
authors.initials: AL
authors.lastname: Perraud
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Traystman
authors.forename: Paco S
authors.initials: PS
authors.lastname: Herson
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009919:Orchiectomy; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism; D012727:Sex Characteristics; D015398:Signal Transduction; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D013196:Dihydrotestosterone; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases